tbuckley/cabot-search huggingface dataset:
Acute Pancreatitis: Diagnosis and Treatment
Authors: Peter Szatmary, Tassos Grammatikopoulos, Wenhao Cai, Wei Huang, Rajarshi Mukherjee, Chris Halloran, Georg Beyer, Robert Sutton
Journal: Drugs (2022)

Acute pancreatitis is a common indication for hospital admission, increasing in incidence, including in children, pregnancy and the elderly. Moderately severe acute pancreatitis with fluid and/or necrotic collections causes substantial morbidity, and severe disease with persistent organ failure causes significant mortality. The diagnosis requires two of upper abdominal pain, amylase/lipase ≥ 3 ×upper limit of normal, and/or cross-sectional imaging findings. Gallstones and ethanol predominate while hypertriglyceridaemia and drugs are notable among many causes. Serum triglycerides, full blood count, renal and liver function tests, glucose, calcium, transabdominal ultrasound, and chest imaging are indicated, with abdominal cross-sectional imaging if there is diagnostic uncertainty. Subsequent imaging is undertaken to detect complications, for example, if C-reactive protein exceeds 150 mg/L, or rarer aetiologies. Pancreatic intracellular calcium overload, mitochondrial impairment, and inflammatory responses are critical in pathogenesis, targeted in current treatment trials, which are crucially important as there is no internationally licenced drug to treat acute pancreatitis and prevent complications. Initial priorities are intravenous fluid resuscitation, analgesia, and enteral nutrition, and when necessary, critical care and organ support, parenteral nutrition, antibiotics, pancreatic exocrine and endocrine replacement therapy; all may have adverse effects. Patients with local complications should be referred to specialist tertiary centres to guide further management, which may include drainage and/or necrosectomy. The impact of acute pancreatitis can be devastating, so prevention or reduction of the risk of recurrence and progression to chronic pancreatitis with an increased risk of pancreas cancer requires proactive management that should be long term for some patients.
Ewing Sarcoma and Osteosarcoma Have Distinct Immune Signatures and Intercellular Communication Networks
Authors: Anthony R. Cillo, Elina Mukherjee, Nathanael G. Bailey, Sayali Onkar, Jessica Daley, Claudia Salgado, Xiang Li, Dongyan Liu, Sarangarajan Ranganathan, Melissa Burgess, John Sembrat, Kurt Weiss, Rebecca Watters, Tullia C. Bruno, Dario A.A. Vignali, Kelly M. Bailey
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Ewing sarcoma and osteosarcoma are primary bone sarcomas occurring most commonly in adolescents. Metastatic and relapsed disease are associated with dismal prognosis. Although effective for some soft tissue sarcomas, current immunotherapeutic approaches for the treatment of bone sarcomas have been largely ineffective, necessitating a deeper understanding of bone sarcoma immunobiology. Experimental Design: Multiplex immunofluorescence analysis of immune infiltration in relapsed versus primary disease was conducted. To better understand immune states and drivers of immune infiltration, especially during disease progression, we performed single-cell RNA sequencing (scRNAseq) of immune populations from paired blood and bone sarcoma tumor samples. Results: Our multiplex immunofluorescence analysis revealed increased immune infiltration in relapsed versus primary disease in both Ewing sarcoma and osteosarcoma. scRNAseq analyses revealed terminally exhausted CD8+ T cells expressing co-inhibitory receptors in osteosarcoma and an effector T-cell subpopulation in Ewing sarcoma. In addition, distinct subsets of CD14+CD16+ macrophages were present in Ewing sarcoma and osteosarcoma. To determine pathways driving tumor immune infiltration, we conducted intercellular communication analyses and uncovered shared mechanisms of immune infiltration driven by CD14+CD16+ macrophages and unique pathways of immune infiltration driven by CXCL10 and CXCL12 in osteosarcoma. Conclusions: Our study provides preclinical rationale for future investigation of specific immunotherapeutic targets upon relapse and provides an invaluable resource of immunologic data from bone sarcomas.
UNCAN.eu, a European Initiative to UNderstand CANcer
Authors: Eric Solary, Patricia Blanc, Michael Boutros, Charis Girvalaki, Franco Locatelli, Rene H. Medema, Péter Nagy, Josep Tabernero
Journal: Cancer Discovery (2022)

Summary: “UNCAN.eu” refers to a collective European effort seeking to enable a leap forward in our understanding of cancer. This initiative, which includes the creation of a European cancer research data hub, will pave the way to new advances in cancer care. Starting on September 1, 2022, a 15-month coordination and support action will generate a blueprint for UNCAN.eu. Here, we summarize the cancer research issues that the blueprint will propose to tackle at the European level.
Genomic Characteristics and Single-Cell Profiles After Immunotherapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma
Authors: Pei Dong, Xinyue Zhang, Yulu Peng, Yijun Zhang, Ruiqi Liu, Yilin Li, Qiwen Pan, Wensu Wei, Shengjie Guo, Zhiling Zhang, Hui Han, Fangjian Zhou, Yang Liu, Liru He
Journal: Clinical Cancer Research (2022)

Fumarate hydratase-deficient renal cell carcinoma (FHRCC) is highly malignant, but the urgent need for effective treatment remains unmet. We aimed to analyze the genomic characteristics and microenvironment of FHRCC and the cause of heterogeneous response to immune checkpoint inhibitor (ICI)-based treatment at single-cell level.Whole-exome sequencing and IHC staining analyses were performed in 30 advanced FHRCC patients. Single-cell RNA sequencing following ICI-based treatment was conducted in 4 patients. The clinical characteristics, therapeutic effect, and follow-up data were analyzed.The median tumor mutation burden was only 0.14 mutations per megabase. IHC staining showed an immune-active tumor microenvironment characterized by extensive CD8+ T-cell infiltration. ATM expression was inversely correlated with percentage of tumor-infiltrating CD8+ T cells. Trajectory analysis indicated gradually upregulated exhausted markers and an increased apoptotic trend of CD8+ T cells despite continuous exposure to ICI-based treatment. ICI-based treatment was associated with improved overall response rate (17.6% vs. 0%, P = 0.046) and disease control rate (DCR; 64.7% vs. 12.5%, P = 0.004) compared with tyrosine kinase inhibitor. Among patients with germline mutation, the ORR (16.7% vs. 0%, P = 0.086) and the DCR (66.7% vs. 14.3%, P = 0.011) were higher after ICI-based treatment.Immune infiltration is frequent in FHRCC. ICI-based treatment is a promising regimen, and treatment response depends on the functional status of tumor-infiltrating lymphocytes. ICI-based treatment cannot reverse the exhaustion of CD8+ T cells in patients with progressive disease, highlighting the need for additional therapeutic strategies.
Heavy Rainfall and HIV and Sexually Transmitted Infections in Sub-Saharan Africa—Potential New Risk
Authors: Kristie L. Ebi, Euphemia Sibanda
Journal: JAMA Network Open (2022)

Jason M. Nagata, MD, MSc; Karly Hampshire, BS; Adrienne Epstein, PhD; Feng Lin, MS; Jennifer Zakaras, MPH; Pamela Murnane, PhD; Edwin D. Charlebois, PhD; Alexander C. Tsai, MD, PhD; Denis Nash, PhD; Sheri D. Weiser, MD, MPH
ImmunoPET Imaging with 89Zr-Labeled Atezolizumab Enables <i>In Vivo</i> Evaluation of PD-L1 in Tumorgraft Models of Renal Cell Carcinoma
Authors: Aditi Mulgaonkar, Roy Elias, Layton Woolford, Bing Guan, Kien Nham, Payal Kapur, Alana Christie, Vanina T. Tcheuyap, Nirmish Singla, I. Alex Bowman, Christina Stevens, Guiyang Hao, James Brugarolas, Xiankai Sun
Journal: Clinical Cancer Research (2022)

Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 and its ligand (PD-1/PD-L1) have transformed the treatment paradigm for metastatic renal cell carcinoma (RCC). However, response rates to ICIs as single agents or in combination vary widely and predictive biomarkers are lacking. Possibly related to the heterogeneity and dynamic nature of PD-L1 expression, tissue-based methods have shown limited value. Immuno-positron emission tomography (immunoPET) may enable noninvasive, comprehensive, and real-time PD-L1 detection. Herein, we systematically examined the performance of immunoPET for PD-L1 detection relative to IHC in an RCC patient-derived tumorgraft (TG) platform.Eight independent RCC TGs with a wide range of PD-L1 expression (0%-85%) were evaluated by immunoPET. Uptake of 89Zr-labeled atezolizumab ([89Zr]Zr-DFO-ATZ) was compared with PD-L1 expression in tumors by IHC through double-blind analyses. Clinical outcomes of ICI-treated patients whose TGs were examined were analyzed to evaluate the clinical role of immunoPET in RCC.ImmunoPET with [89Zr]Zr-DFO-ATZ (day 6/7 postinjection) revealed a statistically significant association with PD-L1 IHC assays (P = 0.0014; correlation ρXY = 0.78). Furthermore, immunoPET can be used to assess the heterogeneous distribution of PD-L1 expression. Finally, studies in the corresponding patients (n = 4) suggest that PD-L1 signal may influence ICI responsiveness.ImmunoPET with [89Zr]Zr-DFO-ATZ may enable a thorough and dynamic assessment of PD-L1 across sites of disease. The power of immunoPET to predict ICI response in RCC is being explored in an ongoing clinical trial (NCT04006522).
Phosphoglycerate mutase 5 initiates inflammation in acute kidney injury by triggering mitochondrial DNA release by dephosphorylating the pro-apoptotic protein Bax
Authors: Jingyao Li, Xi’ang Sun, Ninghao Yang, Jiayun Ni, Hongyan Xie, Hengjiang Guo, Xin Wang, Li Zhou, Jun Liu, Sijia Chen, Xiaoxia Wang, Yingying Zhang, Chen Yu, Wei Zhang, Limin Lu
Journal: Kidney International (2022)
Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases
Authors: Sheheryar Kabraji, Jing Ni, Sarah Sammons, Tianyu Li, Amanda E.D. Van Swearingen, Yanzhi Wang, Alyssa Pereslete, Liangge Hsu, Pamela J. DiPiro, Chris Lascola, Heather Moore, Melissa Hughes, Akshara S. Raghavendra, Maria Gule-Monroe, Rashmi K. Murthy, Eric P. Winer, Carey K. Anders, Jean J. Zhao, Nancy U. Lin
Journal: Clinical Cancer Research (2022)

Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized.We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases.T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1-resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3-16.2) months, with 42% (7/17) remaining on treatment at data cutoff.T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted. See related commentary by Soffietti and Pellerino, p. 8.
Circulating Tumor and Immune Cells for Minimally Invasive Risk Stratification of Smoldering Multiple Myeloma
Authors: Rosalinda Termini, David Žihala, Evangelos Terpos, Albert Perez-Montaña, Tomáš Jelínek, Marc Raab, Niels Weinhold, Elias K. Mai, Anna Luise Grab, Jill Corre, Francois Vergez, Antonio Sacco, Marco Chiarini, Viviana Giustini, Alessandra Tucci, Sara Rodriguez, Cristina Moreno, Cristina Perez, Catarina Maia, Esperanza Martín-Sánchez, Camilla Guerrero, Cirino Botta, Juan-Jose Garces, Aitziber Lopez, Luis-Esteban Tamariz-Amador, Felipe Prosper, Joan Bargay, Maria-Elena Cabezudo, Enrique M. Ocio, Roman Hájek, Joaquin Martinez-Lopez, Fernando Solano, Rebeca Iglesias, Artur Paiva, Catarina Geraldes, Helena Vitoria, Clara Gomez, Felipe De Arriba, Heinz Ludwig, Antoni Garcia-Guiñon, Maria Casanova, Adrian Alegre, Valentin Cabañas, Maialen Sirvent, Albert Oriol, Javier de la Rubia, José-Ángel Hernández-Rivas, Luis Palomera, Maria Sarasa, Pablo Rios, Noemi Puig, Maria-Victoria Mateos, Juan Flores-Montero, Alberto Orfao, Hartmut Goldschmidt, Hervé Avet-Loiseau, Aldo M. Roccaro, Jesus F. San-Miguel, Bruno Paiva
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under- and overtreatment. We hypothesized that replacing bone marrow (BM) plasma cells (PC) for circulating tumor cells (CTC), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model. Experimental Design: We report the outcomes of 150 patients with SMM enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of 3 years since enrollment. Results: Patients with &amp;gt;0.015% versus ≤0.015% CTCs at baseline had a median time-to-progression of 17 months versus not reached (HR, 4.9; P &amp;lt; 0.001). Presence of &amp;gt;20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio &amp;gt;20, &amp;gt;2 g/dL M-protein, and &amp;gt;0.015% CTCs. The 20/2/20 and 20/2/0.015 models yielded similar risk stratification (C-index of 0.76 and 0.78). The combination of the 20/2/0.015 model with an immune risk score based on the percentages of SLAN+ and SLAN− nonclassical monocytes, CD69+HLADR+ cytotoxic NK cells, and CD4+CXCR3+ stem central memory T cells, allowed patient’ stratification into low, intermediate-low, intermediate-high, and high-risk disease with 0%, 20%, 39%, and 73% rates of progression at 2 years. Conclusions: This study showed that CTCs outperform BM PCs for assessing tumor burden. Additional analysis in larger series are needed to define a consensus cutoff of CTCs for minimally invasive stratification of SMM.
Author Correction: A low-power stretchable neuromorphic nerve with proprioceptive feedback
Authors: Yeongjun Lee, Yuxin Liu, Dae-Gyo Seo, Jin Young Oh, Yeongin Kim, Jinxing Li, Jiheong Kang, Jaemin Kim, Jaewan Mun, Amir M. Foudeh, Zhenan Bao, Tae-Woo Lee
Journal: Nature Biomedical Engineering (2022)
Change in the Parent-Clinician Relationship Throughout the First Year of Treatment in Pediatric Oncology
Authors: Jennifer W. Mack, Tim Jaung, Hajime Uno, Julienne Brackett
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Challenges in the therapeutic relationship between clinicians and parents of children with cancer have been shown to emerge immediately after diagnosis, but little is known about whether such relationships improve over time. <h3>Objective</h3> To better understand the potential evolution of parent-clinician relationships over the first year after diagnosis of pediatric cancer. <h3>Design, Setting, and Participants</h3> This survey study was conducted from November 2015 to September 2020 at Dana-Farber Cancer Institute/Boston Children’s Hospital and Texas Children’s Hospital. Participants were oncology clinicians (attending physicians and fellows or nurse practitioners) and parents of children (aged &lt;18 years) with a cancer diagnosis. Surveys were completed at study enrollment (soon after diagnosis [baseline]) and at the 3-month and 12-month follow-up. <h3>Exposures</h3> Children had to have had at least 3 previous clinical visits with a primary oncology clinician. <h3>Main Outcomes and Measures</h3> Survey instruments included the parent and clinician versions of the Relationship Challenges Scale, and factors associated with changes in relationships, including parental, clinician, and health care system attributes, were measured. <h3>Results</h3> Survey participants included 150 parents (118 women [78.7%]; 98 with White race and ethnicity [65.3%]) and 49 clinicians (39 [79.6%] women; 39 with White race and ethnicity [79.6%]). Parents reported on 175 relationships with clinicians, and clinicians reported on 98 relationships with parents at all 3 time points (baseline, 3-month follow-up, and 12-month follow-up). Of the 175 relationships, 33 (18.9%) were considered to be challenging by parents at baseline, 27 (15.4%) were considered to be challenging at the 3-month follow-up, and 32 (18.3%) were considered to be challenging at the 12-month follow-up. Of the 33 challenging relationships at baseline, 20 (60.6%) resolved at the 12-month follow-up, whereas 13 (39.4%) had persistent challenges. However, 19 relationships that were not challenging at baseline had new challenges at the 12-month follow-up, corresponding to 59.4% of all challenges at the 12-month follow-up. No clinician behaviors were associated with improvement. Strategies used frequently (≥50%) by clinicians in their relationships that were associated with improvement included holding family meetings, apologizing, adapting to the parent’s communication style, and devoting extra time and attention. <h3>Conclusions and Relevance</h3> Results of this study showed that some parents experienced challenging relationships with their child’s oncology clinicians beginning at diagnosis and throughout the first year after diagnosis. Although many such relationships improved, others worsened, reflecting the vulnerable and stressful nature of parent-clinician relationships.
Analysis of Heavy Rainfall in Sub-Saharan Africa and HIV Transmission Risk, HIV Prevalence, and Sexually Transmitted Infections, 2005-2017
Authors: Jason M. Nagata, Karly Hampshire, Adrienne Epstein, Feng Lin, Jennifer Zakaras, Pamela Murnane, Edwin D. Charlebois, Alexander C. Tsai, Denis Nash, Sheri D. Weiser
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Extreme precipitation, including heavy rains and flooding, is associated with poor health outcomes mediated in part by decreases in income and food production. However, the association between heavy rains and HIV burden is unknown. <h3>Objective</h3> To investigate the association between heavy rainfall, HIV prevalence, and HIV transmission risk over a 12-year span in sub-Saharan Africa. <h3>Design, Setting, and Participants</h3> A cross-sectional population-based study, using data collected from the 2005-2017 Demographic and Health Surveys, was conducted in 21 countries in sub-Saharan Africa and analyzed from July 29, 2021, to June 14, 2022. <h3>Exposures</h3> Heavy rainfall was defined based on the extent to which annual rainfall deviated from the historical average (standardized precipitation index ≥1.5) at the enumeration area level. <h3>Main Outcomes and Measures</h3> HIV, self-reported sexually transmitted infections (STIs), and number of sexual partners. <h3>Results</h3> The study included 288 333 participants aged 15 to 59 years; 172 344 were women (59.8%), and 183 378 were married (63.6%). Mean (SD) age was 31.9 (10.0) years. Overall, 42.4% of participants were exposed to at least 1 year of heavy rainfall in the past 10 years. Each year of heavy rainfall was associated with 1.14 (95% CI, 1.11-1.18) times the odds of HIV infection and 1.11 (95% CI, 1.07-1.15) times the odds of an STI in the past 12 months. There was also an association between heavy rainfall and the reported number of sexual partners (incident rate ratio, 1.12; 95% CI, 1.10-1.15). The odds were greater for the association between heavy rainfall and HIV prevalence and STIs among participants aged older than 20 years and participants in rural areas. <h3>Conclusions and Relevance</h3> The findings of this study suggest that heavy rainfall was associated with a higher HIV burden in sub-Saharan Africa. The association between heavy rainfall and STIs and number of sexual partners suggests that an increase in the risk of sexual transmission is a plausible mechanism for the observed findings around HIV prevalence. Heavy rainfall could also worsen food insecurity, increasing the risk of transactional sex, or cause damage to public health infrastructure, reducing access to STI education, HIV testing, and treatment.
Nemvaleukin alfa, a novel engineered IL-2 fusion protein, drives antitumor immunity and inhibits tumor growth in small cell lung cancer
Authors: Yuanwang Pan, Yuan Hao, Han Han, Ting Chen, Hailin Ding, Kristen E Labbe, Elaine Shum, Kayla Guidry, Hai Hu, Fiona Sherman, Ke Geng, Janaye Stephens, Alison Chafitz, Sittinon Tang, Hsin-Yi Huang, Chengwei Peng, Christina Almonte, Jared E Lopes, Heather C Losey, Raymond J Winquist, Vamsidhar Velcheti, Hua Zhang, Kwok-Kin Wong
Journal: Journal for ImmunoTherapy of Cancer (2022)

Small cell lung cancer (SCLC) is a deadly disease with a 5-year survival of less than 7%. The addition of immunotherapy to chemotherapy was recently approved as first-line treatment; however, the improved clinical benefit is modest, highlighting an urgent need for new treatment strategies. Nemvaleukin alfa, a novel engineered interleukin-2 fusion protein currently in phase I-III studies, is designed to selectively expand cytotoxic natural killer (NK) cells and CD8+ T cells. Here, using a novel SCLC murine model, we investigated the effects of a mouse version of nemvaleukin (mNemvaleukin) on tumor growth and antitumor immunity.A novel Rb1-/-p53-/-p130-/- SCLC model that mimics human disease was generated. After confirming tumor burden by MRI, mice were randomized into four treatment groups: vehicle, mNemvaleukin alone, chemotherapy (cisplatin+etoposide) alone, or the combination of mNemvaleukin and chemotherapy. Tumor growth was measured by MRI and survival was recorded. Tumor-infiltrating lymphocytes and peripheral blood immune cells were analyzed by flow cytometry. Cytokine and chemokine secretion were quantified and transcriptomic analysis was performed to characterize the immune gene signatures.mNemvaleukin significantly inhibited SCLC tumor growth, which was further enhanced by the addition of chemotherapy. Combining mNemvaleukin with chemotherapy provided the most significant survival benefit. Profiling of tumor-infiltrating lymphocytes revealed mNemvaleukin expanded the total number of tumor-infiltrating NK and CD8+ T cells. Furthermore, mNemvaleukin increased the frequencies of activated and proliferating NK and CD8+ T cells in tumors. Similar immune alterations were observed in the peripheral blood of mNemvaleukin-treated mice. Of note, combining mNemvaleukin with chemotherapy had the strongest effects in activating effector and cytotoxic CD8+ T cells. mNemvaleukin alone, and in combination with chemotherapy, promoted proinflammatory cytokine and chemokine production, which was further confirmed by transcriptomic analysis.mNemvaleukin, a novel cytokine-based immunotherapy, significantly inhibited murine SCLC tumor growth and prolonged survival, which was further enhanced by the addition of chemotherapy. mNemvaleukin alone, and in combination with chemotherapy, drove a strong antitumor immune program elicited by cytotoxic immune cells. Our findings support the evaluation of nemvaleukin alone or in combination with chemotherapy in clinical trials for the treatment of SCLC.